Paget's disease of bone is a disease of unknown etiology in which bone resorption is abnormally accelerated in the pelvis, the femur, the skull, etc., and thereby symptoms such as bone deformation and ostealgia develop. Treating agents presently used for Paget's disease of bone are bisphosphonate formulations and calcitonin formulations, which are also used as osteoporosis treating agents. But, the former has poor taking compliance since the necessary administration dose is 4 to 5 times the administration dose for an osteoporosis patient, and the later has a disadvantageous point that sufficient suppression of bone resorption is not exhibited. Further, these formulations are nosotropic drugs resting on the basis of the bone resorption suppressing activity of the agents and can not completely cure the disease.
It has recently been made clear that osteoclast precursor cells collected from a patient of Paget's disease of bone have 1α, 25-dihydroxyvitamin D3 receptors, and the sensitivity of the precursor cells to 1α,25-dihydroxyvitamin D3 is stronger by 10 to 100 times that of the osteoclast precursor cells in a normal person (J. Bone Miner. Res., 15, 228-236 (2000)). Further, the blood concentration of 1α, 25-dihydroxyvitamin D3 in a patient of Paget's disease of bone being same as in a normal person, the sthenia of bone resorption by endogenic 1α, 25-dihydroxyvitamin D3 is supposed to play an important role to the onset of Paget's disease of bone. Thus, a compound which suppresses the action of 1α,25-dihydroxyvitamin D3 on osteoclast precursor cells, that is, a compound like a vitamin D antagonist, can suppress the bone resorption accelerated in a patient of Paget's disease of bone more completely, and it is expected that the compound has a therapeutic effect superior to that of a presently used bone resorption-suppressing agent.
On the other hand, hypercalcemia develops when vitamin D production is accelerated by various kinds of diseases such as lymphoma (Blood, vol. 82, 1383-1394 (1993)), tuberculosis (N. Ingl. J. Med., vol. 311, 1683-1685 (1984)), sarcoidosis (J. Clin. Endocrinol. Metab., vol. 60, 960-966 (1985)), candidosis (Am. J. Med., vol. 74, 721-724 (1983), granuloma (Am. J. Nephrol., vol. 13, 275-277 (1993)), leprosy (Ann. Intern Med., vol. 105, 890-891 (1986)), primary hyperparathyroidism and a malignant tumor. Since it is known that the blood calcium concentration is increased by the action of an active vitamin D3, a compound antagonistic to the action of an active vitamin D3, that is, a vitamin D3 antagonist is considered to be effective for treating hypercalcemia.
Further, a vitamin D3 antagonist is considered to be effective also as a treating agent for osteoporosis. In this disease, the bone quantity decreases as a result of bone resorption overcoming osteogenesis, and this disease often develops after menopause or with aging. A bisphosphonate, a vitamin D3 derivative, estrogen, calcitonin or the like is used as a treating agent for osteoporosis. Further, a parathyroid hormone (PTH) formulation which has such strong osteogenesis stimulating effect as not observed heretofore has appeared on clinical fields recently, and it becomes possible for patients of osteoporosis to receive more effective pharmacotherapy. However, being an injection, the PTH formulation has troubles in convenience, drug compliance, price and the like. Accordingly, if an agent which is not expensive can have an activity equivalent to PTH by oral administration, it may become a useful agent. Incidentally, the secretion of PTH is controlled by blood calcium or 1α,25-dihydroxyvitamin D3, an active vitamin D3, and the quantity of the secretion of PTH increases with decreasing concentration of such a component. Hence, a compound which is antagonistic to the activity of 1α,25-dihydroxyvitamin D3, that is, a vitamin D3 antagonist accelerates PTH secretion, and it is expected for the compound to exhibit an effect similar to the above mentioned PTH formulation.
By the way, in the abstract (published on Nov. 5, 2002) of the 22nd symposium on medicinal chemistry and the 11th annual meeting of division of medicinal chemistry in the Pharmaceutical Society of Japan, a pair of compounds which are expressed by the below-mentioned formula (1) were disclosed. One compound has R1=R2=Me, and the other compound has R1=Bn and R2=Me, in the formula. However, the former is not included in the present invention, and the disclosure of the latter was made by the inventors of the present invention, and the above-mentioned provisional application, on which the present invention is based, had been made within one year from the disclosure. Therefore, the novelty of the present invention is not rejected. Further, in the disclosure, there was no suggestion on the vitamin D3 antagonist activity.
Further, in the description of International Publication WO00/24712, vitamin D3 derivatives having a lactam structure on the side chain were disclosed. However, their chemical structures are different from the compounds of the present invention in that the nitrogen atom in the lactone ring is not substituted, and the substituents of the 25-position do not include a hydroxyl group. The antagonist activity to a vitamin D3 was not suggested also in this disclosure.
As vitamin D3 derivatives having an antagonist activity to vitamin D3, compounds described in the descriptions of International Publication WO95/33716, International Publication WO03/070716, International Publication WO94/07853, International Publication WO97/00242 and International Publication WO97/41096 are known. However, they are clearly different from the compounds of the present invention in their chemical structure; that is, the compounds described in the first two have α-ethoxymethylene lactone structures at the side chain, and the compounds described in the last three have 22-ene-24-hydroxy structures at the side chain.
Further, vitamin D3 derivatives having the antagonist activity to vitamin D3 were also disclosed in the description of International Publication WO03/000634; however, they are different from the compounds of the present invention in that the derivatives have ester groups bound to the 1-position.
It is known that vitamin D3 derivatives have various kinds of interesting physiological activities, and variegated vitamin D3 derivatives have been synthesized heretofore by a number of researchers. Nevertheless, antagonist activities to vitamin D3 have been observed only in these three groups which have no commonality to each other and cover a narrow range. That is, it can be said that no findings have been accumulated heretofore regarding relations between chemical structures of vitamin D3 derivatives and antagonist activities to vitamin D3. Even though an antagonist activity to vitamin D3 is observed in a vitamin D3 compound, an antagonist activity to vitamin D3 can not be expected in a compound having a structure slightly different from the compound.